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Predicting onset and course of adolescent depression with sleep and cortisol measures
THURSDAY, MAY 18
BIOL PSYCHIATRY 595 1995;37:593-683
8. PREDICTING ONSET AND COURSE OF ADOLESCENT DEPRESSION WITH SLEEP AND CORTISOL MEASURES
10. ELECTRO-CONVULSIVE TREATMENT (ECT) IN REFRACTORY ADOLESCENT DEPRESSION
U. Rao, R.E. Dahl, N. D. Ryan, B. Birmaher, D. E. Williamson, & R. Rao
N. Ghaziuddin, C. King, M. Naylor, M. Ghaziuddin, N. Chaudhary, & J. Greden
University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, P A 15101
University of Michigan, Ann Arbor, MI 48109-0390
This study examined EEG sleep and baseline plasma cortisol predictors of differential outcome in adulthood in 26 adolescent subjects with unipolar major depressive disorder (MDD) and 33 normal controls. The subjects (15.4 + 1.3 years) initially participated in sleep and neuroendocrine studies. Clinical course was assessed for the interval period 6-8 years later using "blind" standardized assessments. The MDD sample was divided by clinical outcome into those with no further episodes (n = 6), those with unipolar recurrent course (n - 15), and those who switched to bipolar disorder (n = 5). The controls were separated into those with no lifetime psychiatric disorder (n - 23) and those who developed depression (n = 7). Subjects with bipolar course were separated, and the remaining groups were compared on initial sleep and cortisol parameters as potential predictors of clinical course. MDD subjects with recurrent unipolar course had reduced REM latency (76.8 + 31.2 vs. 104.1 _+48.2, p _<0.07), increased REM density (1.4 5:_ 0.2 vs. 1.1 + 0.3, p <_ 0.01) and elevated cortisol around sleep onset (10.8 +_4.7 vs. 6.7 +_2.7, p _< 0.01) compared to controls with no disorder. Controls who developed depression had reduced REM latency (67.3 +_20.2 vs. 104.1 + 48.2,p <_0.08) and increased REM density (1.5 5:0.3 vs. 1.1 +_0.3, p < 0.005) compared to controls with no disorder. MDD subjects with no further episodes were similar to MDD subjects with recurrent unipolar course on REM latency (81.0 5: 45.4) and REM density (1.3 5: 0.4); however, cortisol around sleep onset discriminated unipolar subjects with no further episodes from those with recurrent unipolar course (7.3 + 5.3 vs. 10.8 + 4.7, p _< 0.06). EEG sleep and baseline cortisol may be helpful in predicting the differential clinical course of adolescent MDD. Reduced REM latency and increased REM density may predict a new onset of depression. Elevated cortisol around sleep onset may predict recurrences in adolescents with unipolar MDD.
Infrequent use of ECT in adolescents with affective disorders indicates absence of objective data to establish its efficacy and safety. Because of lack of well established efficacious pharmacological treatments, ECT is an option which should be considered. We studied 7 hospitalized adolescent females with a primary DSM Ill-R diagnosis of affective disorder (MDD = 5; bipolar, depressed - 1; organic mood disorder - 1), and mean age 16 years (SD = 1.2). All subjects had failed to respond to three or more adequate trials of antidepressant pharmacotherapy. After thorough diagnostic evaluation including diagnostic interview, neuropsychological evaluation, neurology consultation, and 24-hour observation, subjects were offered treatment with ECT. Consent from parent/legal guardian and assent of the adolescent were obtained. ECT treatment was commenced with nondominant right electrode placement (six subjects) or bilateral (one subject with organic mood disorder). Due to lack of adequate response, electrode placement was changed to bilateral for three subjects. Significant improvement was noted on Children Depression Rating Scores, t - 2.83, p < 0.05, and the Global Assessment of Functioning Scale, t = -7.17, p < 0.05. Assessment of cognitive functioning using the Mini Mental State Examination showed no significant decline in cognitive functioning. Side effects noted were headache (100%), prolonged seizures (75%), after recovery seizures (14%). Minor side effects were common. After recovery, seizures were rare but are a potentially serious complication. We conclude that ECT can be an effective treatment for depressed adolescents who have failed to respond to antidepressant pharmacotherapy.
11. MELATONIN AFFECTS THE PROCESSING OF [3-AMYLOID PRECURSOR PROTEIN IN CELL LINES
9. PHARMACOLOGICAL ALGORITHMS FOR TREATMENT RESISTANT DEPRESSION IN CHILDREN AND ADOLESCENTS
D.K. Lahiri, W. Song, & J.I. Numberger, Jr.
N. Alessi
Laboratory o f Molecular Neurogenetics, Institute o f Psychiatric Research, Program o f Medical Neurobiology, Department o f Psychiatry, Indiana University School o f Medicine, Indianapolis, IN 46202
University of Michigan, Child and Adolescent Psychiatry, Ann Arbor, MI 48109 Treatment-resistant depression inw)lves up to 40% of adults with major depression. Medication trials, their duration, and augmentation strategies involving adults have been discussed at length. The prevalence and nature of treatment-resistant depression in children and adolescents is just beginning to be appreciated. For children and adolescents, the same experience does not exist in either the identification or treatment of treatment-resistant depression. A review of current treatment and follow-up studies would suggest that there exists such a population, although its frequency is study dependent. This paper will deal with the topic of treatment-resistant depression in children and adolescence, their identification, and treatment. Postulated algorithms for the selection of medications and augmentation strategies will be presented and compared to those offered in the treatment of adults with treatment-resistant depression. Case examples and case series utilizing a wide range of strategies will be presented and critiqued. Particular emphasis will be placed on the identification of comorbid conditions as a means to determine medication selection among this group.
Alzheimer disease (AD) patients display irregularities in the pattern of normal circadian rhythms. In addition to the hypothalamus, Alzheimertype pathology has been reported in the superchiasmatic nuclei, the site of the circadian oscillator. The disruption of circadian regulation by brain grafts that overexpress amyloid beta-peptide (A[~P) has been reported. We examined the relationship between the pineal hormone melatonin, which is secreted in mammals during the dark phase of the circadian cycle, and the processing of beta-amyloid precursor protein ([3APP). AD is characterized by depositions of A[~P in the brain in the form of extracellular plaques and cerebrovascular amyloid. AI3P (Mr.-4 kDa) is derived from a family of large [~APP molecules (Mr.-110 kDa) which are integral membrane glycoproteins. Soluble derivatives of AI3P and l A P P lacking the cytoplasmic tail, transmembrane domain, and a small portion of the extracellular domain are generated by [3APP secretases. Using cell cultures, we analyzed the level of [3APP in glial, fibroblast, pheochromocytoma, and neuroblastoma cells by immunoblotting cell lysates and conditioned media. Normal levels of secretion of soluble 13APPderivatives by cells into conditioned media were severely inhibited by treating cells with
BIOL PSYCHIATRY 595 1995;37:593-683
8. PREDICTING ONSET AND COURSE OF ADOLESCENT DEPRESSION WITH SLEEP AND CORTISOL MEASURES
10. ELECTRO-CONVULSIVE TREATMENT (ECT) IN REFRACTORY ADOLESCENT DEPRESSION
U. Rao, R.E. Dahl, N. D. Ryan, B. Birmaher, D. E. Williamson, & R. Rao
N. Ghaziuddin, C. King, M. Naylor, M. Ghaziuddin, N. Chaudhary, & J. Greden
University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, P A 15101
University of Michigan, Ann Arbor, MI 48109-0390
This study examined EEG sleep and baseline plasma cortisol predictors of differential outcome in adulthood in 26 adolescent subjects with unipolar major depressive disorder (MDD) and 33 normal controls. The subjects (15.4 + 1.3 years) initially participated in sleep and neuroendocrine studies. Clinical course was assessed for the interval period 6-8 years later using "blind" standardized assessments. The MDD sample was divided by clinical outcome into those with no further episodes (n = 6), those with unipolar recurrent course (n - 15), and those who switched to bipolar disorder (n = 5). The controls were separated into those with no lifetime psychiatric disorder (n - 23) and those who developed depression (n = 7). Subjects with bipolar course were separated, and the remaining groups were compared on initial sleep and cortisol parameters as potential predictors of clinical course. MDD subjects with recurrent unipolar course had reduced REM latency (76.8 + 31.2 vs. 104.1 _+48.2, p _<0.07), increased REM density (1.4 5:_ 0.2 vs. 1.1 + 0.3, p <_ 0.01) and elevated cortisol around sleep onset (10.8 +_4.7 vs. 6.7 +_2.7, p _< 0.01) compared to controls with no disorder. Controls who developed depression had reduced REM latency (67.3 +_20.2 vs. 104.1 + 48.2,p <_0.08) and increased REM density (1.5 5:0.3 vs. 1.1 +_0.3, p < 0.005) compared to controls with no disorder. MDD subjects with no further episodes were similar to MDD subjects with recurrent unipolar course on REM latency (81.0 5: 45.4) and REM density (1.3 5: 0.4); however, cortisol around sleep onset discriminated unipolar subjects with no further episodes from those with recurrent unipolar course (7.3 + 5.3 vs. 10.8 + 4.7, p _< 0.06). EEG sleep and baseline cortisol may be helpful in predicting the differential clinical course of adolescent MDD. Reduced REM latency and increased REM density may predict a new onset of depression. Elevated cortisol around sleep onset may predict recurrences in adolescents with unipolar MDD.
Infrequent use of ECT in adolescents with affective disorders indicates absence of objective data to establish its efficacy and safety. Because of lack of well established efficacious pharmacological treatments, ECT is an option which should be considered. We studied 7 hospitalized adolescent females with a primary DSM Ill-R diagnosis of affective disorder (MDD = 5; bipolar, depressed - 1; organic mood disorder - 1), and mean age 16 years (SD = 1.2). All subjects had failed to respond to three or more adequate trials of antidepressant pharmacotherapy. After thorough diagnostic evaluation including diagnostic interview, neuropsychological evaluation, neurology consultation, and 24-hour observation, subjects were offered treatment with ECT. Consent from parent/legal guardian and assent of the adolescent were obtained. ECT treatment was commenced with nondominant right electrode placement (six subjects) or bilateral (one subject with organic mood disorder). Due to lack of adequate response, electrode placement was changed to bilateral for three subjects. Significant improvement was noted on Children Depression Rating Scores, t - 2.83, p < 0.05, and the Global Assessment of Functioning Scale, t = -7.17, p < 0.05. Assessment of cognitive functioning using the Mini Mental State Examination showed no significant decline in cognitive functioning. Side effects noted were headache (100%), prolonged seizures (75%), after recovery seizures (14%). Minor side effects were common. After recovery, seizures were rare but are a potentially serious complication. We conclude that ECT can be an effective treatment for depressed adolescents who have failed to respond to antidepressant pharmacotherapy.
11. MELATONIN AFFECTS THE PROCESSING OF [3-AMYLOID PRECURSOR PROTEIN IN CELL LINES
9. PHARMACOLOGICAL ALGORITHMS FOR TREATMENT RESISTANT DEPRESSION IN CHILDREN AND ADOLESCENTS
D.K. Lahiri, W. Song, & J.I. Numberger, Jr.
N. Alessi
Laboratory o f Molecular Neurogenetics, Institute o f Psychiatric Research, Program o f Medical Neurobiology, Department o f Psychiatry, Indiana University School o f Medicine, Indianapolis, IN 46202
University of Michigan, Child and Adolescent Psychiatry, Ann Arbor, MI 48109 Treatment-resistant depression inw)lves up to 40% of adults with major depression. Medication trials, their duration, and augmentation strategies involving adults have been discussed at length. The prevalence and nature of treatment-resistant depression in children and adolescents is just beginning to be appreciated. For children and adolescents, the same experience does not exist in either the identification or treatment of treatment-resistant depression. A review of current treatment and follow-up studies would suggest that there exists such a population, although its frequency is study dependent. This paper will deal with the topic of treatment-resistant depression in children and adolescence, their identification, and treatment. Postulated algorithms for the selection of medications and augmentation strategies will be presented and compared to those offered in the treatment of adults with treatment-resistant depression. Case examples and case series utilizing a wide range of strategies will be presented and critiqued. Particular emphasis will be placed on the identification of comorbid conditions as a means to determine medication selection among this group.
Alzheimer disease (AD) patients display irregularities in the pattern of normal circadian rhythms. In addition to the hypothalamus, Alzheimertype pathology has been reported in the superchiasmatic nuclei, the site of the circadian oscillator. The disruption of circadian regulation by brain grafts that overexpress amyloid beta-peptide (A[~P) has been reported. We examined the relationship between the pineal hormone melatonin, which is secreted in mammals during the dark phase of the circadian cycle, and the processing of beta-amyloid precursor protein ([3APP). AD is characterized by depositions of A[~P in the brain in the form of extracellular plaques and cerebrovascular amyloid. AI3P (Mr.-4 kDa) is derived from a family of large [~APP molecules (Mr.-110 kDa) which are integral membrane glycoproteins. Soluble derivatives of AI3P and l A P P lacking the cytoplasmic tail, transmembrane domain, and a small portion of the extracellular domain are generated by [3APP secretases. Using cell cultures, we analyzed the level of [3APP in glial, fibroblast, pheochromocytoma, and neuroblastoma cells by immunoblotting cell lysates and conditioned media. Normal levels of secretion of soluble 13APPderivatives by cells into conditioned media were severely inhibited by treating cells with